PMID- 27245569 OWN - NLM STAT- MEDLINE DCOM- 20171101 LR - 20220316 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 21 IP - 6 DP - 2016 Jun TI - Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization. PG - 762-70 LID - 10.1634/theoncologist.2015-0497 [doi] AB - INTRODUCTION: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. MATERIALS AND METHODS: Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. RESULTS: A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. CONCLUSION: Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing. CI - (c)AlphaMed Press. FAU - Ali, Siraj M AU - Ali SM AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu. FAU - Hensing, Thomas AU - Hensing T AD - Department of Medicine, North Shore University Health System, Evanston, Illinois, USA Department of Medicine, The University of Chicago, Chicago, Illinois, USA. FAU - Schrock, Alexa B AU - Schrock AB AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Allen, Justin AU - Allen J AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Sanford, Eric AU - Sanford E AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Gowen, Kyle AU - Gowen K AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Kulkarni, Atul AU - Kulkarni A AD - Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. FAU - He, Jie AU - He J AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Suh, James H AU - Suh JH AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Lipson, Doron AU - Lipson D AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Elvin, Julia A AU - Elvin JA AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Yelensky, Roman AU - Yelensky R AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Chalmers, Zachary AU - Chalmers Z AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Chmielecki, Juliann AU - Chmielecki J AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Peled, Nir AU - Peled N AD - Davidoff Cancer Center, Tiqwa, Israel. FAU - Klempner, Samuel J AU - Klempner SJ AD - Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Orange, California, USA. FAU - Firozvi, Kashif AU - Firozvi K AD - Maryland Hematology-Oncology, Wheaton, Maryland, USA. FAU - Frampton, Garrett M AU - Frampton GM AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Molina, Julian R AU - Molina JR AD - Mayo Clinic, Rochester, Minnesota, USA. FAU - Menon, Smitha AU - Menon S AD - Froedtert Cancer Center, Milwaukee, Wisconsin, USA. FAU - Brahmer, Julie R AU - Brahmer JR AD - Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. FAU - MacMahon, Heber AU - MacMahon H AD - Department of Radiology, The University of Chicago, Chicago, Illinois, USA. FAU - Nowak, Jan AU - Nowak J AD - Department of Pathology, North Shore University Health System, Evanston, Illinois, USA. FAU - Ou, Sai-Hong Ignatius AU - Ou SH AD - Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Orange, California, USA. FAU - Zauderer, Marjorie AU - Zauderer M AD - Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA. FAU - Ladanyi, Marc AU - Ladanyi M AD - Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA. FAU - Zakowski, Maureen AU - Zakowski M AD - Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA. FAU - Fischbach, Neil AU - Fischbach N AD - Bridgeport Oncology, Bridgeport, Connecticut, USA. FAU - Ross, Jeffrey S AU - Ross JS AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA Albany Medical College, Albany, New York, USA. FAU - Stephens, Phil J AU - Stephens PJ AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Miller, Vincent A AU - Miller VA AD - Foundation Medicine Inc., Cambridge, Massachusetts, USA. FAU - Wakelee, Heather AU - Wakelee H AD - Department of Medicine, Division of Oncology, School of Medicine, Stanford University, Stanford, California, USA. FAU - Ganesan, Shridar AU - Ganesan S AD - Cancer Institute of New Jersey, New Brunswick, New Jersey, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu. FAU - Salgia, Ravi AU - Salgia R AD - Department of Medicine, The University of Chicago, Chicago, Illinois, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Case Reports PT - Journal Article DEP - 20160531 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyridines) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM CIN - Oncologist. 2016 Jun;21(6):662-3. PMID: 27245570 MH - Adult MH - Aged MH - Anaplastic Lymphoma Kinase MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics MH - Crizotinib MH - Female MH - Gene Expression Profiling MH - *Gene Rearrangement MH - Genomics MH - Humans MH - In Situ Hybridization, Fluorescence/*methods MH - Lung Neoplasms/*drug therapy/genetics MH - Male MH - Protein Kinase Inhibitors/*therapeutic use MH - Pyrazoles/*therapeutic use MH - Pyridines/*therapeutic use MH - Receptor Protein-Tyrosine Kinases/*genetics PMC - PMC4912370 OTO - NOTNLM OT - ALK OT - Crizotinib OT - Fluorescence in situ hybridization OT - Fusion OT - Genomic profiling COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2016/06/02 06:00 MHDA- 2017/11/02 06:00 PMCR- 2017/06/01 CRDT- 2016/06/02 06:00 PHST- 2015/12/07 00:00 [received] PHST- 2016/03/07 00:00 [accepted] PHST- 2016/06/02 06:00 [entrez] PHST- 2016/06/02 06:00 [pubmed] PHST- 2017/11/02 06:00 [medline] PHST- 2017/06/01 00:00 [pmc-release] AID - theoncologist.2015-0497 [pii] AID - T15497 [pii] AID - 10.1634/theoncologist.2015-0497 [doi] PST - ppublish SO - Oncologist. 2016 Jun;21(6):762-70. doi: 10.1634/theoncologist.2015-0497. Epub 2016 May 31.